Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

An Ad5[E1-, E2b-]-HER2/neu vector induces immune responses and inhibits HER2/neu expressing tumor progression in Ad5 immune mice

Abstract

Immunotherapy is a promising approach for the treatment of cancers. Modified adenovirus 5 (Ad5) vectors have been used as a platform to deliver genes encoding tumor associated antigens (TAA). A major obstacle to Ad5 vector immunotherapy has been the induction of vector immunity following administration or the presence of pre-existing Ad5 immunity, which results in vector mitigation. It has been reported by us that the Ad5[E1-, E2b-] platform with unique deletions in the E1, E2b and E3 regions can induce potent cell mediated immunity (CMI) against delivered transgene products in the presence of pre-existing Ad5 immunity. Here we report the use of an Ad5[E1-, E2b-] vector platform expressing the TAA HER2/neu as a breast cancer immunotherapeutic agent. Ad5[E1-, E2b-]-HER2/neu induced potent CMI against HER2/neu in Ad5 naïve and Ad5 immune mice. Humoral responses were also induced and antibodies could lyse HER2/neu expressing tumor cells in the presence of complement in vitro. Ad5[E1-, E2b-]-HER2/neu prevented establishment of HER2/neu-expressing tumors and significantly inhibited progression of established tumors in Ad5 naïve and Ad5 immune murine models. These data demonstrate that in vivo delivery of Ad5[E1-, E2b-]-HER2/neu can induce anti-TAA immunity and inhibit progression of HER2/neu expressing cancers.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Higano CS, Schellhammer PF, Small EJ, Burch PA, Nemunaitis J, Yuh L et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer 2009; 115: 3670–3679.

    Article  CAS  Google Scholar 

  2. Romano G, Pacilio C, Giordano A . Gene transfer technology in therapy: current applications and future goals. Stem Cells 1999; 17: 191–202.

    Article  CAS  Google Scholar 

  3. Kirk CJ, Hartigan-O’Connor D, Mule JJ . The dynamics of the T-cell anitumor response: chemokine-secreting dendritic cells can prime tumor-reactive T cells extranodally. Cancer Res 2001; 61: 8794–8802.

    CAS  PubMed  Google Scholar 

  4. Kirk CJ, Hartigan-O’Connor D, Nickoloff BJ, Chamberlain JS, Giedlin M, Aukerman L et al. T cell-dependant antitumor immunity mediated by secondary lympoid tissue chemokine: augmentation of dendrtitic cell-based immunotherapy. Cancer Res 2001; 61: 2062–2070.

    CAS  PubMed  Google Scholar 

  5. Polo JM, Dubensky Jr TW . Virus-based vectors for human vaccine applications. Drug Discov Today 2002; 7: 719–727.

    Article  CAS  Google Scholar 

  6. Liniger M, Zuniga A, Naim HY . Use of viral vectors for the development of vaccines. Expert Rev Vaccines 2007; 6: 255–266.

    Article  CAS  Google Scholar 

  7. Gaydos CA, Gaydos JC . Adenovirus vaccine. In: Orenstein WA (eds). Vaccines, 4th edn. Sauders: Philadelphia, 2004, pp 863–885.

    Google Scholar 

  8. Butterfield LH, Jilani SM, Chakraborty NG, Bui LA, Ribas A, Dissette VB et al. Generation of melanoma-specific cytotoxic T lymphocytes by dendritic cells transduced with a MART-1 adenovirus. J Immunol 1998; 161: 5607–5613.

    CAS  PubMed  Google Scholar 

  9. Diao J, Smythe JA, Smyth C, Rowe PB, Alexander IE . Human PBMC-derived dendritic cells transduced with an adenovirus vector induce cytotoxic T-lymphocyte responses against a vector-encoded antigen in vitro. Gene Ther 1999; 6: 845–853.

    Article  CAS  Google Scholar 

  10. Dietz AB, Vuk-Pavlovic S . High efficiency adenovirus-mediated gene transfer to human dendritic cells. Blood 1998; 91: 392–398.

    CAS  PubMed  Google Scholar 

  11. Ishida T, Chada S, Stipanov M, Nadaf S, Ciernik FI, Gabrilovich DI et al. Dendritic cells transduced with wild-type p53 gene elicit potent anti-tumour immune responses. Clin Exp Immunol 1999; 117: 244–251.

    Article  CAS  Google Scholar 

  12. Ribas A, Butterfield LH, McBride WH, Jilani SM, Bui LA, Vollmer CM et al. Genetic immunization for the melanoma antigen MART-1/Melan-A using recombinant adenovirus-transduced murine dendritic cells. Cancer Res 1997; 57: 2865–2869.

    CAS  PubMed  Google Scholar 

  13. Arthur JF, Butterfield LH, Roth MD, Bui LA, Kiertscher SM, Lau R et al. A comparison of gene transfer methods in human dendritic cells. Cancer Gene Ther 1997; 4: 17–25.

    CAS  PubMed  Google Scholar 

  14. Rea D, Schagen FH, Hoeben RC, Mehtali M, Havenga MJ, Toes RE et al. Adenoviruses activate human dendritic cells without polarization toward a T-helper type 1-inducing subset. J Virol 1999; 73: 10245–10253.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Hirschowitz EA, Weaver JD, Hidalgo GE, Doherty DE . Murine dendritic cells infected with adenovirus vectors show signs of activation. Gene Ther 2000; 7: 1112–1120.

    Article  CAS  Google Scholar 

  16. Loser P, Jennings GS, Strauss M, Sandig V . Reactivation of the previously silenced cytomegalovirus major immediate-early promoter in the mouse liver: involvement of NF-Kappa-B. J Virol 1998; 72: 180–190.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Morelli AE, Larregina AT, Ganster RW, Zahorchak AF, Plowey JM, Takayama T et al. Recombinant adenovirus induces maturation of dendritic cells via an NF-KappaB-dependent pathway. J Virol 2000; 74: 9617–9628.

    Article  CAS  Google Scholar 

  18. Wan Y, Emtage P, Foley R, Carter R, Gauldie J . Murine dendritic cells transduced with an adenoviral vector expressing a defined tumor antigen can overcome anti-adenovirus neutralizing immunity and induce effective tumor regression. Int J Oncol 1999; 14: 771–776.

    CAS  PubMed  Google Scholar 

  19. McCoy K, Tatsis N, Korioth-Schmitz B, Lasaro MO, Hensley SE, Lin SW et al. Effect of preexisting immunity to adenovirus human serotype 5 antigens on the immune responses of nonhuman primates to vaccine regimens based on human- or chimpanzee-derived adenovirus vectors. J Virol 2007; 81: 6594–6604.

    Article  CAS  Google Scholar 

  20. Kresge KJ . Clinical trials yield promising results from two adenovirus-based vaccines. IAVI Rep 2005; 9: 24.

    Google Scholar 

  21. Nwanegbo E, Vardas E, Gao W, Whittle H, Sun H, Rowe D et al. Prevalence of neutralizing antibodies to adenoviral serotypes 5 and 35 in adult populations of The Gambia, South Africa and the United States. Clin Diagn Lab Immunol 2004; 11: 351–357.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Gabitzsch ES, Xu Y, Yosida L, Balint J, Amalfitano A, Jones FR et al. A preliminary and comparative evaluation of a novel Ad5[E1-, E2b-] recombinant based vaccine used to induce cell mediated immune responses. Immuno Lett 2009; 122: 44–51.

    Article  CAS  Google Scholar 

  23. Papp Z, Babiuk LA, Baca-Estrada ME . The effect of pre-existing adenovirus-specific immunity on immune responses induced by recombinant adenovirus expressing glycoprotein D of bovine herpesvirus type 1. Vaccine 1999; 17: 933–943.

    Article  CAS  Google Scholar 

  24. Amalfitano A, Hauser MA, Hu H, Serra D, Begy CR, Chamberlain JS . Production and characterization of improved adenovirus vectors with the E1, E2b, and E3 genes deleted. J Virol 1998; 72: 926–933.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Hodges BL, Serra D, Hu H, Begy CA, Chamberlain JS, Amalfitano A . Multiply deleted [E1, polymerase-, and pTP-] adenovirus vector persists despite deletion of the preterminal protein. J Gene Med 2000; 2: 250–259.

    Article  CAS  Google Scholar 

  26. Hu H, Serra D, Amalfitano A . Persistence of an [E1-, polymerase-] adenovirus vector despite transduction of a neoantigen into immune-competent mice. Hum Gene Ther 1999; 10: 355–364.

    Article  CAS  Google Scholar 

  27. Osada T, Yang XY, Hartman ZC, Glass O, Hodges BL, Niedzwiecki D et al. Optimization of vaccine responses with an E1, E2b, E3-deleted Ad5 vector circumvents pre-existing anti-vector immunity. Cancer Gene Ther 2009; 16: 673–682.

    Article  CAS  Google Scholar 

  28. Everett RS, Hodges BL, Ding EY, Xu F, Serra D, Amalfitano A . Liver toxicities typically induced by first- generation adenoviral vectors can be reduced by use of E1, E2b-deleted adenoviral vectors. Hum Gene Ther 2003; 14: 1715–1726.

    Article  CAS  Google Scholar 

  29. Gabitzsch ES, Xu Y, Balint Jr JP, Hartman ZC, Lyerly HK, Jones FR . Anti-tumor immunotherapy despite immunity to adenovirus using a novel adenoviral vector Ad5[E1-, E2b-]-CEA. Cancer Immunol Immunother 2010; 59: 1131–1135.

    Article  CAS  Google Scholar 

  30. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL . Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987; 235: 177–182.

    Article  CAS  Google Scholar 

  31. Paik S, Hazan R, Fisher ER, Sass RE, Fisher B, Redmond C et al. Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: prognostic significance of erbB-2 protein overexpression in primary breast cancer. J Clin Oncol 1990; 8: 103–112.

    Article  CAS  Google Scholar 

  32. Disis ML, Gooley TA, Rinn K, Davis D, Piepkorn M, Cheever MA et al. Generation of T-cell immunity to the HER-2/neu protein after active immunization with HER-2/neu peptide-based vaccines. J Clin Oncol 2002; 20: 2624–2632.

    Article  CAS  Google Scholar 

  33. Peoples GE, Holmes JP, Hueman MT, Mittendorf EA, Amin A, Khoo S et al. Combined clinical trial results of a HER2/neu (E75) vaccine for the prevention of recurrence in high-risk breast cancer patients: U.S. Military Cancer Institute Clinical Trials Group Study I-01 and I-02. Clin Cancer Res 2008; 14: 797–803.

    Article  CAS  Google Scholar 

  34. Gabitzsch ES, Xu Y, Yoshida LH, Balint J, Amalfitano A, Jones FR . Novel adenovirus type 5 vaccine platform induces cellular immunity against HIV-1 Gag, Pol, Nef despite the presence of Ad5 immunity. Vaccine 2009; 27: 6394–6398.

    Article  CAS  Google Scholar 

  35. Hartman ZC, Wei J, Osada T, Glass O, Lei G, Yang XY et al. An adenoviral vaccine encoding full-length inactivated human Her2 exhibits potent immunogenicity and enhanced therapeutic efficacy without oncogenicity. Clin Cancer Research 2010; 16: 1466–1477.

    Article  CAS  Google Scholar 

  36. Helguera G, Rodriguez JA, Penichet ML . Cytokines fused to antibodies and their combinations as therapeutic agents against different peritoneal HER2/neu expressing tumors. Mol Cancer Ther 2006; 5: 1029–1040.

    Article  CAS  Google Scholar 

  37. Balint Jr JP, Jones FR . Detection of elevated levels of antiidiotypic antibody levels in immune thrombocytopenic patients expressing antiplatelet antibody. Blood 1994; 84: 664–665.

    PubMed  Google Scholar 

  38. Carlsson G, Gullberg B, Hafstrom L . Estimation of tumor volume using different formulas—an experimental study in rats. J Cancer Res Clin Oncol 1983; 105: 20–23.

    Article  CAS  Google Scholar 

  39. Appledorn DM, Kiang A, McBride A, Jiang H, Seregin S, Scott JM et al. Wild-type adenoviruses from groups A-F evoke unique innate immune responses, of which HAd3 and SAd23 are partially complement dependent. Gene Ther 2008; 15: 885–901.

    Article  CAS  Google Scholar 

  40. Seregin SS, Amalfitano A . Overcoming pre-existing adenovirus immunity by genetic engineering of adenovirus-based vectors. Expert Opin Biol Ther 2009; 9: 1521–1531.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was funded in part by NIH-NCI grant 1R43CA139663-01. We acknowledge ViraQuest Inc for amplification of the vaccines. The authors thank Dr Winston Witcomb for management and care of the animals. We also thank Carol Jones for management of the grant activities and Susan Nguyen for assistance in preparation of the paper.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to E S Gabitzsch.

Ethics declarations

Competing interests

Frank R Jones work has been funded in part by the National Cancer Institutes and Etubics Corporation. All authors are employees of Etubics Corporation and are funded in part by grants from the National Cancer Institute.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gabitzsch, E., Xu, Y., Balcaitis, S. et al. An Ad5[E1-, E2b-]-HER2/neu vector induces immune responses and inhibits HER2/neu expressing tumor progression in Ad5 immune mice. Cancer Gene Ther 18, 326–335 (2011). https://doi.org/10.1038/cgt.2010.82

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cgt.2010.82

Keywords

This article is cited by

Search

Quick links